Antibacterial compositions



United States Patent 0 ice 3,193,453 ANTTBACTEREAL CGWOSITIONS HerbertQuinn, ycamore Township, Ohio, assignor to The Procter & Gamble Company,Cincinnati, Ohio, a corporation of Ohio No Drawing. Filed Get. 1, i962,Ser. No. 227,584 1 Claim. (Cl. 1161-30) This invention concernsantibacterial compositions consisting of a mixture of antibacterialagents which exhibit 1 enhanced antibacterial activity when used incombination with each other. More specifically this invention relates toa mixture of one or more commonly used bisphenol antibacterial agents asdescribed more fully herein in combination with certainimino-imidazolidines, the mixture exhibiting enhanced antibacterialactivity and particularly when incorporated into a soap, or detergentproduct formulation.

In recent years there has been a markedly increased usage of soaps anddetergent products containing antibacterial agents by housewives andother consumers. This is due principally to the increased awareness bythe consumer of the need to maintain and insurehealthful livingconditions. Many compounds have been suggested in past years for use asantibacterial agents in soaps, detergents, shampoos, and othersurfactant based compositions; most of those compounds suggested,however, had some serious deficiencies which limited their utility. Suchdeficiencies were, for instance, ineffectiveness in soap solution, toogreat a toxicity, photosensitivity, and effective halogenatedcarbanilide's, halogenated bisphenols and the' halogenatedsalicylanilides have been disclosed. The synergism or enhanced activityprovides a higher level of antibacterial effectiveness for an equalamount of anti bacterial agent used, or more important, it enables amanufacturer to use a lesser amount of antibacterial agents yet retain arelatively high degree of effectiveness, thereby enabling a lessexpensive product to be manufactured. This would be particularly helpfulwhen the bisphenols are being used, as the discoloration of the soapcaused by photosensitivity of this antibacterial agent 'is almostdirectly proportional to the amount of agent used, i.e., the higher theamount used, the greater the discoloration. It is significant to notethat effective synergistic combinations of antibacterial agents orcombinations which show enhanced activity are relatively rare and whensuch combinations are discovered, the synergism or enhancement isentirely unpredictable. It should be appreciated, therefore, that thereis a need for still more effective antibacterial agents and combinationsof agents having greater activity than has previously been known andwhich can be incorporated into soaps, detergent com- 3,193,453 PatentedJuly 6, 1965 positions and other formulations without substantiallirnitations. I

It is therefore an object of this invention to provide antibacterialcompositions having enhanced activity which possess a high level ofantibacterial effectiveness.

It is a further object of this invention to provide antibacterialcompositions which are effective in a soap or detergent product medium.

It is a still further object of this invention to provide antibacterialcompositions which are economical and which do not have significantdiscoloration problems or toxicity problems.

Other objects and improvements will become apparent from the followingdescription.

In accordance with this invention, it has been found that mixtures of(A) halogenated bisphenols and (B) substituted imino-imidazolidines, ashereinafter more fully described, exhibit enhanced antibacterialactivity and particularly when incorporated into a fatty acid soap orsynthetic anionic, nonionic, ampholytic or amph'oteric detergentcomposition at a ratio of (A) to (B) ranging from about 5:1 to about1:5.

As used herein enhanced activity means antibacterial activity that isgreater than would be expected if the compounds acted independently whenused as the same total percentage level.

The substituted bisphenols used in the mixtures described herein havethe general formula:

OH OH Xll X where X is a halogen and n is an integer from 1 to 3inclusive, and R is selected from the group consisting of alkyleneradicals having from 1 to 4 carbon atoms and divalent sulfur.

Halogenated bisphenols which find utility in this invention are, forexample, those disclosed in US. Patent 2,535,077, K-unz et al., andinclude bis-(Z-hydroxy- 3,5,6-trichloro phenyl)methane andbis-(2-hydroxy-3,5- dichloro phenyl)methane. Other suitable bisphenolsinclude, for example, bis-(2-hydroxy-3,5,6-trichlorophenyl)- sulfide andbis-(2-hydroxy-3,S-dichlorophenyl)-sulfide.

The substituted imino-imidazolidine compounds used in the mixtures ofthis invention have the general formula:

wherein R is an alkyl radical having from 12 to about 18 carbon atomsand R is selected from the group consisting of hydrogen, and .alkylradicals .having from 1 to 6 carbon atoms.

These compounds are disclosed in US. Patent 2,999,-

047, Model et 'al. Those compounds which find particular usefulness are,for example, l-dodecyl-Z-imino-imidazolidine hydrochloride,1-tetradecyl-2-imino-imidazolidine hydrochloride,1-dodecyl-3-butyl-2-iminoimidazolir 3 dine hydrochloride,l:dodecyl-E.-cyclohexyl-2-iminoimidazolidine hydrochloride,l-tetradecyl-3-acetic acid-2- iminoimidazol'idine hydrochloride, and1-dodecyl-3-acetic acid-Z-iminoimidazolidine hydrochloride.

The following combinations of antibacterial agents are illustrative ofthe mixtures of this invention possessing enhancedactivity but shouldnot be considered as limiting the scope of the invention.

Ratio of parts Cloth protection test Total Anti- Bacterial bacterialColonies Sur- Compound Agent (s) as Ratio viving Per Percent in Sq. In.Cloth, BSD 1 S. aureus .25 1, 500 IMD .05 1,917 1 1 9 I v 1 B- G''11 1171 1,792 o. rMD+G-n 1,408 1)., Detergent (Control) 2,192 E. Water wash2,142

EXAMPLE II In this example the enhancedactivity of the combinations ofthisinvention is'shown by means of the Standard Tube Dilution Test,which consists essentially of preparing serial dilutions of theantibacterial composi- 1-dodecyl-2-iinino-imidazolidine hydrochloride 3Bis (2-hydroxy-3, l,6-trichlorophenyl)methane l V1-tetradecyl-2-imino-imidazolidine hydrochloride 4Bis(2-l1ydroxy-3,S-dichlorophenyl) sulfide 1l-dodecyl-imirio-imidazolidine hydrochloride 1Bis(2-hydroxy-3,S-chlorophenyl) methane 1l-tetradecyl-Z-imino-imidazolidine hydrochloride 2 Bis(2-hydroxy3,5,6atrichlorophenyl) sulfide 3 1-tetradecyl-Z-imino-irhidazolidinehydrochloride ,3 Bis(2-hydroxy-3,S-dichlorophenyl) sulfide 11-tetradecyl-3-butyl-2 imino-imidazolildine hydrochloride 5Bis(Z-hydroxy-3,5 chlorophenyl methane 1- l-tetradecyl-3-aceticacid-Z-imino-imidazolidine hydrochloride 1Bis(2-hydroxy-3,5,6rtrichlorophenyl) sulfide 5 l-tetradecyl-3-butylZ-imino-imidazolidine 4. 2 Bis(2-hydroxy-3,5,6-trichlorophenyl) sulfide1 l-octadecyl-2-imino-imidazolidine 1 Bis-(2-hydroxy-3,S-dichlorophenyl)sulfide. 1

It has been found that the above listed combinations and similarvariations thereof possess enhanced antibac terial properties whereby alasting antibacterial efiect is obtained particularly when they .areusedrin fatty acid 7 soap and anionic, nonionic, ampholytic, and'amphoteric V synthetic detergent compositions and other products wherean antibacterial action is desired. This enhanced activity can be morereadily seen by reference to the following examples based onrepresentatives of the above combinations.

EXAMPLE 1 tions to be tested 'in a FDA broth medium, inoculating withthe chosen test organism and observing the weakest sentthe compoundsindicated:

1MB 1-dodecyl-Z-iminoirnidazolidine hydrochlorideG-11bis(2-hydroxy-3,5,6-trichlorophenyl) methane to dry and then theyare planted in an agar medium Petri plate with the inoculated surface upand anfoverlay of nutrient is added over the fabric. The Petri platesare then incubated at 37 C. for 48 hours and thereafter bacterial countsare taken by means of a low-power dis secting microscope; The relativeability of a' treated" figure represents'anaverageof the organisms foundon six replicate cloth swatches. H V In this example the followingletter abbreviations represent'the compounds indicated. i

IMD1dodecyl-2imnioimidazolidine hydrochlorideG-l1bis(2-hydroxy-3,5,6-trichlorophenyl) methane V Bacteriostaticbreakpoints Compound Ratio Totalppm.

S. aureus 1. IMD r 0.9 2. G41 0.11 3. IMD/G-11 1:1 0.14 (EA) Expressedas p.p.m. total quantity of antibacterial agent required to inhibit;growth of S. aureus organism.

(EA) indicates enhanced activity.

the combinations shown. r

.Relatively small amounts of the enhanced antibacterial fmixtures of thepresent invention are sufficient to render soap or detergentcompositions antibacterially active.

.The soap or detergent composition can be in liquid, solid,

. flake, granular 'or other similar form. JA soap or detergentcomposition is termed antibacterial if it is effective in I killing orinhibiting the growth of'the' Staphylococcus aureus organism, whether ornot it happens to be effective against any other type of bacteria. V

Because of the enhanced activity of the mixtures of compounds of thepresent invention, it willbe appreciated that smaller amounts than usualwith conventional antibacterial agents can be incorporated into the soapor detergent compositions and still achieve good antibacterialeffectiveness. Amounts as low as .l% of the enhanced mixtures describedherein have proved satisfactory; however, it is preferred to use amountsof the mixtures ranging from 1% to 2% by total weight of the soap bar ordetergent composition. The upper limit of the amount of agent to be usedis determined by practical and economic considerations and is usuallyabout 5%. The ratios of the agents listed under (A) and (B) supra canrange from about 5:1 to about 1:5 with the preferred ratio being about1: 1.

Generally speaking, an increase in concentration of the mixture havingenhanced activity increases the antibacterial effectiveness of the soapor detergent products. However, it is apparent that the cost of theagent in the soap, detergent composition, or other surfactantformulation mitigates against the use of an excessive amount.Additionally, if too large an amount is incorporated into the soap ordetergent composition, the detergent properties of the product may belessened.

The preferred antibacterial combinations which exhibit the most enhancedactivity for use in this invention includebis-(2-hydroxy-3,S,6-trichlorophenyl) methane in combination with1-dodecyl-2-iminoimidazolidine hydrochloride, andbis-(2-hydroxy-3,5,6-trichlorophenyl) sulfide in combination with1-dodecyl-2-iminoimidazolidine hydrochloride, all at a 1:1 ratio.

The term soap as used herein is meant to designate alkali metal soapssuch as sodium and potassium salts of the higher fatty acids ofnaturally occurring plant or ani mal esters (e.g., palm oil, coconutoil, babassu oil, soybean oil, castor oil, tallow, whale and fish oils,grease and lard, and mixtures thereof). Sodium and potassium soaps canbe made by direct saponification of the fats and the oils or by theneutralization of the free fatty acids which are prepared in a separatemanufacturing process.

The anionic synthetic detergent agent which can be employed with thisinvention is generally defined as a water soluble salt of an organicsulfuric reaction product having as its molecular structure an alkylgroup containing from about 8 to about 22 carbon atoms and a radicalselected from the group consisting of sulfonic acid and sulfuric acidester radicals.

Important examples of the synthetics of this group which can bebenefited through the incorporation therein of the mixtures of thisinvention, are the sodium or potassium alkyl sulfates, especially thosederived by sulfation or" higher alcohols produced by reduction ofglycerides of tallow or coconut oil, sodium or potassium alkyl benzenesulfonates, especially those of the types described in U.S. LettersPatent 2,220,099, granted November 5, 1940, and 2,477,383, granted July26, 1949, in which the alkyl group contains from about 9' to about 15carbon atoms; sodium or potassium alkyl glyceryl ether sulfonates,especially those others in which the alkyl group is derived from thehigher alcohols from tallow or coconut oil; sodium coconut oil fattyacid monoglyceride sulfates and sulfonates, sodium salts of sulfuricacid esters of the reaction product of one mole of a higher fattyalcohol (e.g., tallow or coconut oil alcohols) and about three moles ofethylene oxide, and others known in the art, a number being specificallyset forth in Byerly, U.S. Letters Patent 2,486,921, granted November 1,1949, and Strain,

U.S. Letters Patent 2,486,922, granted November 1, 1949.

Additional anionic surface active sulfonates and sulfates which can beemployed in this invention are the sulfated and sulfonated alkyl acidamides such as Igepon T (C1I7H33CON(CH3)CH2CH2SO3N3.), the sulfated andsulfonated esters such as Igepon AP (RCOOCH CH SO Na) Where R is analkyl radical containing from 11 to 17 carbon atoms) sodium salt of thebisulfate of a dialkyl dicarboxylate, sodium salt of the sulfonic acidderivative of a dialkyl dicarboxylate, sodium sulfosuccinic esters suchas NaOOCCH CH(SO Na) CONHC H and the like.

A minor amount, totaling about 2% of a 1:1 mixture ofbis-(2-hydroxy-3,5,6-trichlorophenyl) methane and 1-dodecyl-Z-imino-imidazolidine hydrochloride for example, renders acomposition containing any of the above detergents or mixtures thereof,antibacterially active against the common organisms found on the skin.

The nonionic synthetic organic detergents which have utility in thepractice of this invention may be broadly defined as compounds producedby the condensation of alkylene oxide groups (hydrophilic in nature)with an organic hydrophobic compound, which may be aliphatic or alkylaromatic in nature. As those skilled in the art are well aware, thelength of the hydrophilic or polyoxyalkylene radical required forcondensation with any particular hydrophobic group can be readilyadjusted to yield a water-soluble compound having the desired degree ofbalance between hydrophilic and hydrophobic elements.

For example, a well known class of nonionics is made available on themarket under the trade name of Pluronic. These compounds are formed bycondensing ethylene oxide with a hydrophobic base formed by thecondensation of propylene oxide with propylene glycol. The hydrophobicportion of the molecule, of course, exhibits water insolubility. Itsmolecular weight is of the order of 1500 to 1800. The addition ofpolyoxyethylene radicals to this hydrophobic portion tends to increasethe water solubility of the molecule as a whole. Liquid prodnets areobtained up to the point where polyoxyethylene content is about 50% ofthe total Weight of the condensation product.

Suitable nonionics also include the polyethylene oxid condensates oralkyl phenols, e.g., the condensation products of alkyl phenols havingfrom 6 to 12 carbon atoms, either straight chain or branch chain, in thealkyl group with ethylene oxide in amounts equal to 10 to 25 moles ofethylene oxide per mole of alkyl phenol. The alkyl substituent in suchcompounds may be derive from polymerized propylene, diisobutylene,octane, or nonane, for example.

Other suitable nonionics may be derived by the condensation of ethyleneoxide with the product resulting from the reaction of propylene oxideand ethylene di amine. Here again, a series of compounds may beproduced, depending on the desired balance between hydrophobic andhydrophilic elements. For example, compounds (molecular weight fromabout 5,000 to about 11,000) of about 40% to polyoxyethylene content andresulting from the reaction of ethylene oxide groups with a hydrophobicbase constituted of the reaction product of ethylene diamine and excesspropylene oxide, said base having a molecular weight of the order of2500 to 3000, are satisfactory.

Further satisfactory nonionics includethe condensation product ofaliphatic alcohols having from 8 to 18 carbon atoms, either straightchain or branch chain, with ethylene oxlde, an example being a coconutalcohol ethylene oxide condensate having from 10 to 30 moles of ethyleneoxide per mole of coconut alcohol, the coconut alcohol fraction havingfrom 10 to 14 carbon atoms.

The ampholytic surface-active detergents which can be used in thepractice of this invention have the general formula RZXM where R is analiphatic hydrophobic group containing from about 8 to about 18 carbons,X is an anion selected from the group consisting of sulfonate, sulfateand carboxy radicals, Z is an intermediate group jointed to R by amember of the group consisting of ether, polyether, ester, amide andamine linkages, and M is a cation to neutralize the charge of the anion.Classification according to whether the detergent has an intermediatelinkage or not is used in Surface Active Agents and Detergents, by A. M.Schwartz, J. W. Perry, and I. Berch, Interscience Publishers, New York,1958, vol. II.

Examples of ampholytic compounds are disodium laurylbeta-iminodipropionate, dipotassium lauryl beta-iminodipropionate andalkyl beta-iminopropionate, where the alkyl group is 'derived from themiddle cut or coconut alcohol or fatty acid.

Other detergent compounds which can be used in th scribed in US. patentapplication No. 163,042 and can be prepared in the manner disclosed inUS. Patent 2,-

129,264 and German Patent 1,018,421. Specific examples are3-(N,N-dimethyl-Nahexadecyl ammonio)-2-hydroxy propane-1 -sulfonate,'.3- (N,N-dimethyl-N-alkyl ammonio Z-hydroxypropane-l-sulfonate, thealkyl group being derived fromtaliow alcohol,3-(N,N-dimethyl-N-dodecylammonio)-propane1-sulfonate, and 3-(N,Ndiethyl-N- hexadecyl ammonio) propane-I-sulfonate.

. The enhanced mixtures of this invention have been found to increasethe antibacterial activity of soap and non-soap synthetic detergentcompositions in bar, liquid, flake, granular and other forms and can beincorporated into the soap or detergent composition by any suitablemethod preferably which yields as a result a uniform dis tribution ofagents throughout the whole mass.

Regular use of a Camay or Ivorytype soap bar conta'ming 1.5% of themixtures of this invention. possessing enhanced activity, e.g., 1%bis(2-hydroxy-3,5,6-tri. chlorophenyl) methane plus .5l-dodecyl-Z-iminoimidaz-olidine hydrochloride results in substantialreductions in the bacterial population of the skin and thereby markedlyreduces body odor attributable to the bacterial deg- 20.5% potassiumalkyl sulfate (alkyl group derived from the middle cut'of alcoholsobtained by the catalytic reduction of coconut oil) p 8.0% sodiumalkyl'glyceryl ether sulfonate (alkyl group derived from the middle cutof alcohols obtained'by catalytic reduction of coconut oil) 33.81%sodium soap of 20:80 coconut:tallow fatty acids 7 17.07% magnesium soapof 20:80 coconutztallow fatty acids 5.81% inorganic salts .75%bis(2-hydroxy-3,'5,6-trichlorophenyl) methane 50%1-tetradecyl-2-iminoimidazolidine ,hydrochlorid 8.0% moisture i Balancemiscellaneous a .This bar exhibits'goododor reducing properties and reduces the numbers of bacteria on the skin and does not discolorsignificantly.

A granular built synthetic detergent compositionhaving the followingformulation can beprepared by spray drying and the antibacterial agentsof this invention can be incorporated therein. This composition impartsconsiderable antibacterial activity to. fabrics washed in the solution.

17.5% sodium alkyl benzene sulfonate (the alkyl radical averaging about12 carbon atoms and being derived from polypropylene),

. 47.9% sodium tripolyphos'phate 13.3% sodium sulfate i 7.0% silicatesolids V .75 bis(Z-hydroxy-3,5-dichlorophenyl) methane .75%1rtetradecyl-2-in1inoimidazolicline Balance water .and miscellaneous Theinvention has been described above in conjunction with variousillustrative examples of antibacterial compositions, toiletand laundrydetergents. It will be obvious to those skilled in the art, however,that the antibacterial mixtures can also be beneficially employed insuch products as shampoos, antiseptic ointment, foot powders, and

the like.

What is claimed is: r 7 An antibacterial composition comprising acombination of (A) bis(2-hydroxy-3,Sfi-trichlorOphenyl) methane and (B)1-dodecyl-2 iminoimidazolidine hydrochloride, the proportions byweight'of (A) and (B) being about 1:1,

said combination displaying'a synergistic antibacterial ac tion Whenused with water from a medium in which the concentration of the saidcombination ranges from about 0.1% to about 0.5% by weight.

References Cited by the Examiner UNITED STATES PATENTS JULIAN s. LEvrrT,Primary Examiner.

J. GREENWALD, Examiner. V

